Nonclassical Antimetabolites XIII

Nonclassical Antimetabolites XXIII

“…An even greater loss in binding occurred when the phosphate group was removed from the nucleotide (4), thus confirming for this enzyme the earlier prediction that the ionized phosphate group of a nucleotide should confer more binding energy than the remaining three oxygen functions of the ribotide moiety (1). In order to show the apparent generality of this finding, a similar study has now been completed with 2'-deoxyuridylate (I), the substrate of thymidylate synthetase, and the results are the subject of this paper.…”

Enzyme Inhibitors XVI

“…Reagents and Assay Procedure.-Adenosine and adenosine deaminase (type I, calf intestinal mucosa) were purchased from the Sigma Chemical Co. The assay procedure for reversible inhibitors has previously been described (1,2,8) and is a modification of the general procedure described by Kaplan (9). The measurements of the initial rates of the enzymic reactions were performed a t 25" in 0.05 Mphosphate buffer at p H 7.6.…”

Factors in the Design of Active-Site-Directed Irreversible Inhibitors

“…Ideally, for chemotherapy the greatest selectivity should be obtained by using an attacking group for the enzymic nucleophilic group that is specific for a single amino acid of the group of 15, thus affording a further dimension of specificity. The phenyl ester group such as that of 5-(carbophenoxyamino)salicylic acid (LI) apparently can only react with a primary amino group, thus having complete functional specificity (35,36). 5-(Carbophenoxyamino) salicylic acid (LI) inactivated GDH at twice the rate of the standard, 4-(iodoacetamido) salicylic acid (XLVI) ; in contrast, LI showed no irreversible inhibition of skeletal muscle LDH (Table I).…”

“…3) to make an irreversible inhibitor for an unexplored enzyme can be gleaned by considering the previous development of irreversible inhibitors of LDH by reading in order the theoretical background (2), types of inhibitors and points of binding (1, X), the noncontact areas (1, 37), and finally the bridge principle (31)(32)(33)(34)(35)(36)49); most of this information has been covered in this review, but not necessarily in the same order. For two enzymes in the folk cofactor area, this approach has been systematically developed to the point where positionings for covalent-forming groups can now be done logically (51-56).…”